Noise Induced Brain Plasticity

ABSTRACT

The present disclosure relates to methods and tools that induce brain plasticity. The method involves presenting to an individual continuous noise over a period of time, and thereafter, providing the individual with tone sensitivity training or language training.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional application Ser.No. 61/359,292, filed on Jun. 28, 2010, which application isincorporated herein by reference in its entirety.

INTRODUCTION

Sensory experiences during the “critical period” have major andlong-lasting impacts on brain processing that have been argued to enableindividuals to adapt to a wide range of environments. In the auditorysystem, there is a well-defined, acoustic environment-dependent criticalperiod in the primary auditory cortex. Within this developmental epoch,cortical representations of spectral, temporal, intensive or combinedfeatures of sound can be greatly distorted (plausibly specialized fortheir representations) by passive exposure to sound stimuli. Theseenvironment-sound-specific changes in selective cortical responses andcortical circuitry are substantially retained into adulthood. Beyond theclosure of the critical period, non-attended or passive exposure tosounds has little plastic consequence for auditory cortex (A1); corticalmodification requires that the older animal be in a learning (attended;rewarded; novel-stimulus) behavioral context.

In this special early epoch, the plasticity of the brain has been arguedto be specifically enabled by immature cortical machinery that operateswith relatively long time and space constants, with temporallyunregulated modulatory facilitation of synaptic plasticity, withphysical synapses and extracellular matrices in an infantile state thatfacilitates synapse mobility and plasticity, and with noisy andtemporally dispersed activities attributable to the still primitivedevelopment of cortical connections and myelin. All of these aspects ofcortical structure and function change (mature) in the transition toadulthood.

Altering the cortical balance of inhibitory-excitatory strengths canresult in a “residual capacity” for critical period-like plasticity inthe adult visual cortex. For example, an epoch of ocular dominanceplasticity mimicking that recorded in the infant brain can be re-openedby maintaining an adult rat for an extended period in the dark.

In the present disclosure, it is shown that post-critical period rats inan environment of moderate-level noise can re-establish a period ofsound exposure-driven plasticity in their primary auditory cortices, andthat this natural functional reversal is accompanied by a complex seriesof parallel changes in the cortex that signal a partial reversal fromthe adult functional status back in the direction of a less-mature A1.

SUMMARY

The present disclosure relates to methods and tools that induce brainplasticity. The method involves presenting to an individual continuousnoise over a period of time, and providing the individual with languagetraining after the presenting step.

Chronic exposure to moderate-level acoustic noise can reverse thematurational changes that mark the infant critical period-to-adulttransition in the primary auditory cortex. Noise exposure then reinstatecritical period plasticity, thus making the auditory cortex morereceptive to subsequent training

BRIEF DESCRIPTION OF FIGURES

FIG. 1. Changes in cortical responses following chronic noise exposure.Panel A, Experimental time lines for noise exposed (NE) and age-matchednaïve control rats. Pw, postnatal week. Panel B, Representativecharacteristic frequency (CF) maps recorded from A1 of NE and controlrats. The color of each polygon in these maps indicates the CF forneurons recorded at that site (see color scales). Polygons are Voronoitessellations representing each neuronal middle-cortical-layer responsesample site, generated so that every point on the cortical surface wasassumed to have the characteristics of its closest neighbors. A,anterior; D, dorsal. Panel C, Comparisons of the percentages of A1 areasthat were tuned to different frequency ranges (left) and the averagereceptive field bandwidths (BW20s; right) between NE and control rats.Bin size=one octave. *, p<0.00012. Error bar represents SEM. Panel D,Average temporal modulation-transfer functions (tMTFs; upper left),average highest temporal rate at which cortical responses were at halfof their maximum (i.e., f_(h1/2) upper right), f_(h1/2) distributions(lower left), and average vector strengths measured at different pulserepetition rates (lower right) for all recordings in NE and controlrats. *, p<0.02-0.00001. Panel E, Average normalized cross-correlationfunctions (left) and Z-score of neuronal firing synchrony as a functionof distance between the two recording sites (right) for NE and controlrats. *, p<0.005.

FIG. 2. Dot raster plots of cortical responses to pulse trains ofdifferent repetition rates recorded from NE (upper) and age-matchednaïve control (lower) rats. The gray horizontal dashes indicate pulseduration. The insert shows tMTF for each raster plot example.

FIG. 3. Average Z-scores of neuronal firing synchrony acrossrepresentative A1 regions for low-(<3.1 kHz), middle-(3.1-9.5 kHz), andhigh-(>9.5 kHz) frequencies for NE and control rats. *, p<0.035-0.00001.Error bar represents SEM.

FIG. 4. Restoration of normal response properties for NE rats afterbeing returned to a normal environment. Panel A, Experimental time linesfor different groups of rats. NE (8 weeks), NE rats that were returnedto a normal auditory environment and mapped at Pw22, i.e., 8 weeks afterthe end of noise exposure. Panel B, Average BW20 and f_(h1/2) of NE ratsmeasured immediately or 8 weeks after noise exposure, illustrating withage-matched naïve control rats. *, p<0.001. Error bar represents SEM.

FIG. 5. Long-term impacts of tone exposure on A1 representation. PanelA, Experimental time lines for different groups of rats. NE+TE (7weeks), NE+TE rats were returned to a normal auditory environment andmapped at Pw22, i.e., 7 weeks after the end of tone exposure. Panel B,Percentages of A1 areas tuned to 7 kHz±0.25 octaves measured at one weekor 7 weeks after the end of the tone exposure, illustrating withage-matched naïve control rats. *, p<0.001 compared to control rats.Error bar represents SEM.

FIG. 6. Noise exposure reinstates critical period plasticity in A1.Panel A, Experimental time lines for noise exposed plus tone exposed(NE+TE), TE-control and age-matched naïve control rats. Panel B,Representative CF maps obtained from NE+TE, TE-control, and controlrats. Outlined polygons indicate recording sites with CF of 7 kHz±0.25octave. Panel C, Distributions of CFs plotted against a normalizedtonotopic axis in different groups of rats. Note that there wereincreased A1 sites that were tuned to 7 kHz in NE+TE rats (dashed line),but not in TE-control rats, when compared to control rats. Panel D,Differences in percentages of A1 areas tuned to different frequencyranges for NE+TE or TE-control rats versus control rats. *,p<0.038-0.00001.

FIG. 7. Noise exposure reinstates cortical period plasticity in A1 ofrats older than one year. Panel A, Representative CF maps showingover-representation of 7 kHz for NE+TE rats older than one year comparedto age-matched NE-control and naïve control rats (see FIG. 6, panel Afor experimental time lines). Panel B, Distributions of CFs plottedagainst a normalized tonotopic axis for NE+TE (N=5), TE-control (N=4)and naïve control (N=5) rats. Panel C, Differences in percentages of A1areas tuned to different frequency ranges for NE+TE or TE-control ratsversus control rats. *, p<0.0001.

FIG. 8. Transient tone exposure beyond the critical period does notalter A1 tonotopy. Panel A, Experimental time lines for different groupsof rats. Note that TE rats were exposed to 7-kHz tones at Pw8 which isthe onset of noise exposure for NE rats (see FIG. 1, panel A). Panel B,Differences in percentages of A1 areas tuned to different frequencyranges for TE (N=4) versus control (N=4) rats. Note that the percentageof A1 area representing each frequency range in TE rats was comparableto that in control rats (t-test, all p>0.3).

FIG. 9. Molecular changes in A1 induced by noise exposure. Panel A,Noise exposure significantly decreased expression levels of GABA_(A) α1and β⅔ in NE rats (N=7) compared to age-matched naïve control rats(N=5). See FIG. 1, panel A for experimental time lines of NE and controlrats. The inserts show representative western blots. Error barrepresents SEM. *, p<0.004. Panel B, Noise exposure did not changeexpression level of AMPA GluR2, or the ratio of NMDA NR2a/NR2b in NErats (N=9) compared to control rats (N=6). Panel C, Noise exposuresignificantly decreased expression level of MBP (N=7 for NE rats and 5for control rats) but increased that of BDNF (N=10 for NE rats and 6 forcontrol rats). *, p<0.04. All but the BDNF values were normalizedagainst control rats.

FIG. 10. Expression levels of GABA_(A) α1 and β⅔ and MBP in the visualcortex. The inserts show representative western blots. Note that nosignificant differences were observed between NE (N=6, 6 and 5,respectively) and control (N=6, 5 and 6, respectively) rats. All valueswere normalized against control rats. Error bar represents SEM.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

The present disclosure relates to methods and tools that induce brainplasticity. The method involves presenting to an individual continuousnoise over a period of time, and providing the individual with languagetraining after the presenting step.

Before the present invention and specific exemplary embodiments of theinvention are described, it is to be understood that this invention isnot limited to particular embodiments described, as such may, of course,vary. It is also to be understood that the terminology used herein isfor the purpose of describing particular embodiments only, and is notintended to be limiting, since the scope of the present invention willbe limited only by the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges is also encompassed within the invention, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either both ofthose included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, exemplarymethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an,” and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “astimulus” includes a plurality of such stimuli and reference to “thesignal” includes reference to one or more signals and equivalentsthereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

Definitions

When describing the methods and compositions of the present disclosure,the following terms have the following meanings unless otherwiseindicated.

The term “cognition”, as used herein, refers to the speed, accuracy andreliability of processing of information, and attention and/or memory.

The term “brain plasticity”, as used herein, refers to the ability ofbrain to learn and/or relearn. Physiological processes that characterizeplasticity involves the changing of neurons, the organization of theirnetworks, and their function, including adding or removing connectionsor neurons.

The term “exposure to noise” or “noise exposure”, as used herein, refersto exposure to audio stimuli that are purely random and can includeexposure to white noise (e.g. structured white noise).

As used herein, the term “white noise” refers to is a random auditorystimulus represented by waveform with a flat power spectral density. Awhite noise auditory signal contains equal power within a fixedbandwidth at any center frequency.

Methods

The present disclosure provides methods and tools to induce brainplasticity. The method involves presenting to an individual continuosnoise (e.g. white noise) over a period of time and, thereafter,providing the individual with tone sensitivity training, languagetraining, and/or any training of the auditory cortex. The presentationof noise to the individual can reverse the maturation of the auditorycortex back to a more plastic state that is amenable to learning. Oncebrain plasticity is increased, the individual is more likely to receiveand learn the training that follows. Essentially, relative to a maturedbrain, increased plasticity can better increase the potential oflearning new skills and/or improving exisiting skills by restructuringneuronal networks. A language training that follows the presentation ofnoise, for example, can train or retrain a person to learn the newlanguage. The individual may find that learning auditory skills, such asa language, can more effective after noise exposure than prior to theexposure.

Where the noise presented to the individual is white noise, the noise isa random auditory stimulus represented by waveform with a flat or mostlyflat power spectral density, in which the power magnitudes are equalwithin a fixed bandwidth at any center frequency. In other words, soundstimuli of various detectable frequencies across a broad spectrum, allwith similar or identical intensity combined can be a type of whitenoise exposed to the individual. Sources and the types of noises arevaried and known in the art and can be used in the subject method. Aslong as the energy level across a broad frequency spectrum isessentially flat, the sound stimulus can be used as white noise in thesubject methods. Broad frequency spectrum can range from about 0.1 toabout 40 kHz, for example. The white noise presented to an individual inthe subject methods can be structured white noise. “Structured whitenoise” or “structured noise” refers to a random or mostly randomauditory stimulus with a non-uniform power spectral density (e.g.Poisson noise, Gaussian noise) and/or with some amount spectro-temporalcorrelations (noise produced by fans, 1000 different people talkingsimultaneously or by automobile traffic on freeways or bridges.

Noise can be synthetically generated by machines, e.g. laboratoryapparatus, or recorded in a natural environment. Common natural sourcesof noises include, 1000 different people simultaneously talking, fans,automobile traffic on freeways or bridges, etc. The type of noise canalso be categorized in terms of its distribution, such as Gaussian,Poisson, etc.

The noise is delivered continuously with a consistentinter-stimulus-interval (ISI). The ISI in pulses of noise is often afraction of a second. The stimulus set can be delivered at a speedmeasured in pulse per seconds (pps). The stimuli in a set can bepresented in about 1, about 2, about 2.5, about 3, about 3.5, about 4,about 5, about 6, about 7, about 8, about 10, about 12, about 15, about20, about 25, up to about 30 or more pps. For example, the noise can bedelivered at 5 pps. The noise can also be delivered at a loudnessappropriate for the individual. Loudness can be expressed in soundpressure level (SPL) measured in decibels (dB) above a standardreference level. The standard reference level is about 20 μPa. Where theauditory stimulus is represented as a waveform, loudness is alsoreferred herein as amplitude. Loudness can range from between about 1 toabout 5, between about 5 to about 10, between about 10 to about 40,between about 40 to about 60, between about 60 to about 70, up to about80 dB or more. For an individual with healthy hearing capability,loudness of the noise should be no more than about 85, no more thanabout 80, no more than about 75 dB or less. For example, in the subjectmethods, the noise can be delivered at a level of about 65 dB.

The duration of noise presentation to the individual can vary (e.g.depending on the magnitude of reversal or the individual). The durationcan be less than 1 week, about 1, about 2, about 3, about 4, about 5,about 6, about 7, about 8, about 9, about 10, about 12, about 15, up toabout 20 weeks or more. For example, the individual can be presentedwith a continuous noise for about 6 weeks.

After the exposure of an individual to continuous noise, the subjectmethods provide language training to the individual. Language trainingencompasses placing the individual in a normal auditory environment orin an environment desirable for the lifestyle of the individual.Language training also includes teaching the subject a new language.Teaching a language can include providing resources for the individualto speak, to read, to converse, to write, or any combination thereof, alanguage. For example, the subject can learn the pronunciation ofvowels, consonants, words and/or syllables. Auditory training relatingto phonemes known in the art and can be applied as language training inthe subject methods. Details can be found in e.g., U.S. Pat. No.6,290,504, U.S. Pat. No. 6,261,101, and U.S. Pat. No. 6,413,098,disclosures of which are incorporated herein by reference. The languagemay be completely previously unknown to the individual or insufficientlylearned prior to employing the methods and tools of the presentdisclosure.

Training provided subsequent to noise exposure also encompasses trainingthat increases sensitivity to a particular auditory frequency range.Exposure of an auditory stimulus in a particular frequency range to aplastic auditory cortex can expand the representation of that frequencyin the auditory cortex. Certain individuals have difficultiesdifferentiating sounds (e.g. frequencies, musical notes, or speechsounds, for example) because of a distorted auditory experience in earlychildhood or secondary to a neurological injury or cochlear injury. Adyslexic individual can also benefit from the subject methods. Forexample, a person who often confuses the sounds ‘b’ and ‘p’ could beexposed to strings of clear, well articulated ‘b’ and ‘p’ sounds atabout 5-10 pps for about 1 week. These and other individuals can resortto trainings of this sort. In another example, if it is desirable for anindividual to increase sensitivity to auditory stimulus of 7 kHz, theindividual may be exposed to a 7 kHz tone at about 5 pps for about 1week. The duration of this tone exposure is no more than about 1%, nomore than about 5%, no more than about 10%, no more than about 20% ormore of the duration of the noise exposure.

Target Population

Individuals who can find use with the methods and tools of the presentdisclosure include people of any age or background where it is desirableto reverse the maturing and un-learn skills of the auditory cortex (e.g.A1). Circumstances where it is desirable include those in whichre-learning from with a plastic state can bring great benefits to theindividual.

One example population that can be targeted by the subject methodsinclude young children who do not develop normal languagerepresentations. The subject methods can be useful for children at agesof less than about 4, less than about 3, less than about 2, less thanabout 1 year of age. For example, the child may be about 20 months old,18 month old, or younger. Sub-optimal language development in childrenmay be caused by substantial early hearing loss. Although the hearingloss may later be recovered, the children may not be able to relearn thelanguage given the maturity stage of their auditory cortex. However, thesubject methods can drive the brain back to a more plastic stage, forexample through the application of a hearing aid or cochlear implant.Deaf children can also benefit from the subject methods for their speechdevelopment can be improved with a plastic auditory cortex.

Abnormal language development may also arise because of early braininjury due to a wide variety of possible causes, or through extremelanguage-exposure deprivation of an environmental (e.g., child of deaf,non-aural parents; very sparse language exposure as recorded, forexample, in Romanian orphans; etc.) or medical (e.g., chronic,persistent middle ear infections) causes. It may arise through corticalepilepsy (a likely cause of regressive language abilities in autisticand other pervasively developmentally disordered children; or inLandau-Kleffner Syndrome and other childhood epilepsy conditions).

The subject methods and tools can also re-start the development oflanguage abilities in impaired, older-aged individuals. Because thesubject methods can reverse maturational processes and therebyre-establish a critical period of development, the environmental ormedical problems that have forestalled normal language or readingdevelopment no longer apply. A language-specific phonemic representationcan be quickly established by exposing the individual to the sounds ofthe language. Language and reading (and associated cognitive) abilitiescan be achieved with more ease for such an individual than one who doesnot employ the subject methods and tools.

Computer System and Tools

The present disclosure provides an apparatus that acts like a hearingaid, except that it carries out the subject method of presenting acontinuous noise (e.g., continuous white noise). The apparatus caninclude a form of cochlear implant, headphones, earphones, loudspeakers,and/or any similar electronic device. The apparatus can include anactuator that generates the continuos noise or language/tone trainingand a power source, optionally any one or more of the following: anamplifier, volume control, and/or some type of coupling to the ear suchas an earmold. Amplifiers take the generated auditory signal and make itlouder. The apparatus can be designed and configured as a behind-the-ear(BTE) hearing aid or inserted directly into the ear canal of a user(e.g. a cochlear implant. The actuator of the apparatus can include oneor more speaker units.

The present disclosure can further contain computer program productsthat can carry out the subject method of inducing brain plasticity. Thesubject matter described herein may be embodied in systems, apparatus,methods, and/or articles depending on the desired configuration. Inparticular, various implementations of the subject methods describedherein may be realized in digital electronic circuitry, integratedcircuitry, specially designed ASICs (application specific integratedcircuits), computer hardware, firmware, software, and/or combinationsthereof. These various implementations may include implementation in oneor more computer programs that are executable and/or interpretable on aprogrammable system including at least one programmable processor, whichmay be special or general purpose, coupled to receive data andinstructions from, and to transmit data and instructions to, a storagesystem, at least one input device (e.g. buttons to turn on or off thewhite noise), and at least one output device (e.g. a speaker inheadphones, earphones, and/or cochlear implant).

These computer programs (also known as programs, software, softwareapplications, applications, components, or code) include machineinstructions for a programmable processor, and may be implemented in ahigh-level procedural and/or object-oriented programming language,and/or in assembly/machine language. The program that executes methodsof the present disclosure may be downloaded to the apparatus (e.g.computer, audio player, cochlear implant, etc.) by the individual from aremote source (server) or be stored in a “machine-readable medium”. Asused herein, the term “machine-readable medium” refers to any computerprogram product, apparatus and/or device (e.g., magnetic discs, opticaldisks, memory, Programmable Logic Devices (PLDs)) used to providemachine instructions and/or data to a programmable processor, includinga machine-readable medium that receives machine instructions as amachine-readable signal.

The apparatus may optionally include one or more networks or othercommunications interfaces, such as a network interface for conveyingtesting or training results to another system or device. The apparatusmay be connected to a computer (e.g. server) or mobile device. Theconnection between the computers and the server can be made via a localarea network (LAN), a wide area network (WAN), open wireless (e.g.Bluetooth™), or through the Internet. The connection of the apparatus toanother computer, for example, can allows information such as the typeof continuous noise, the duration of continuous noise, and any otherdata pertaining to an individual's behavior, physiological (e.g.neurological) changes to be recorded, store, and/or transmitted from onelocation to another, e.g. a server. An administrator can review theinformation, download configuration and data pertaining to a particularindividual, communicate feedback to the individual, and/or transmitinstructions or data back to the individual's apparatus.

The application module executing the subject method may include one ormore of the following: a) a continuous noise generation control program,module or instructions, for generating continuous noise at a selectedsetting, as described above for the subject method; b) an actuatorcontrol program, module, or instructions, for producing or presentingthe continuous noise to an individual; and/or timing device to keeptrack of the duration of the continuous noise exposure; c) a program,module, or instructions for language/tone sensitivity training.

The application module may furthermore store data, which includes themeasurement of physiological data of the individual, and optionally mayalso include analysis results and the like. Any of the programsdescribed above may be stored or executed from more than one locations,e.g. more than one computer readable medium. For example, the continuousnoise generation program may be executed remotely via a network whilethe actuator program may be stored and/or executed locally (e.g.cochlear implant).

As noted above, the subject method can be employed in order to inducebrain plasticity and improve an individual's ability to learn new skillsrelated to the auditory cortex. Although a few variations have beendescribed in detail above, other modifications or additions arepossible. In particular, further features and/or variations may beprovided in addition to those set forth herein. For example, theimplementations described above may be directed to various combinationsand subcombinations of the disclosed features and/or combinations andsubcombinations of several further features disclosed above. Inaddition, the logic flow depicted in the accompanying figures and/ordescribed herein does not require the particular order shown, orsequential order, to achieve desirable results.

In one embodiment, there is provided a computer-readable storage mediumfor inducing brain plasticity in an individual, comprising instructionsexecutable by at least one processing device that, when executed, causethe processing device to: (a) present to the individual with continuousnoise over a period of time; and (b) provide said individual with tonesensitivity training or language training The noise may be structurednoise. The noise may be presented at about 65 dB. The period of time maybe about 6 weeks.

The following examples further illustrate the present invention andshould not be construed as in any way limiting its scope.

EXAMPLES

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

Materials and Methods

The following methods and materials were used in the Examples below.

All experiment procedures were approved under the Institutional AnimalCare and Use Committee (IACUC) at the University of California, SanFrancisco.

Sound Exposure

Rats were placed in sound-shielded test chambers for noise or toneexposure (24 h per d). The continuous broadband noise was generated by arandom noise generator (General Radio Company, Concord, Mass.) andamplified to a calibrated free-field sound level of 65 dB SPL. Theenergy level for noise was essentially flat across a broad frequencyspectrum (0.1-40 kHz). Sound signal for tone exposure was a pulsed 7 kHztone (50 ms duration tone pips with 5 ms ramps at 65 dB SPL, deliveredat 5 pulses per second, pps). There was one second interval of silencebetween every five pulses to minimize adaptation effects. No distortionor substantial harmonic signal was found in the chamber when tonalstimuli were delivered. Rats were given free access to food and waterunder an 8-h light/16-h dark cycle. The weights and activities ofexposed rats were continuously monitored, and compared with naïvecontrol rats. No abnormalities in the behavior of exposed rats could bedetected during sound exposure and their weights were comparable toage-matched naïve rats. Their activities during waking and their sleepbehaviors indicated that the exposure stimuli were not stressful.

Cortical Mapping

Animals were initially anesthetized with an i.p.injection of sodiumpentobarbital (50 mg/kg body weight). Throughout the surgical proceduresand during the recording session, a state of areflexia was maintainedwith supplemental doses of dilute pentobarbital (8 mg/ml) injected i.p.The trachea was cannulated to ensure adequate ventilation and thecisterna magnum drained of cerebrospinal fluid to minimize cerebraledema. The skull was secured in a head holder leaving the earsunobstructed. After reflecting the right temporalis muscle, the auditorycortex was exposed and the dura was resected. The cortex was maintainedunder a thin layer of viscous silicone oil to prevent desiccation.

Cortical responses were recorded with parylene-coated tungstenmicroelectrodes (1-2 megohms at 1 kHz; FHC, Bowdoinham, Me.) in ashielded, double-walled sound chamber. Recording sites were chosen toevenly sample from the auditory cortex while avoiding blood vessels, andwere marked on a magnified digital image of the cortical surfacevasculature. At each recording site the microelectrode was loweredorthogonally into the cortex to a depth of ˜500 μm (layers 4 and 5),where vigorous stimulus-driven responses were recorded. Acoustic stimuliwere generated using TDT System III (Tucker-Davis Technologies, Alachua,Fla.) and delivered to the left ear through a calibrated STAX earphonewith a sound tube positioned inside the external auditory meatus. Asoftware package (SigCal, SigGen, and Brainware; Tucker-DavisTechnologies, Alachua, Fla.) was used to calibrate the earphone,generate acoustic stimuli, monitor cortical response properties online,and store data for offline analysis. The evoked spikes of a neuron or asmall cluster of neurons were collected at each site.

Frequency tuning curves were reconstructed by presenting pure tones of50 frequencies (1-30 kHz, 25 ms duration, 5 ms ramps) at eight soundintensities (0 to 70 dB SPL in 10 dB increments) to the contralateralear in a random, interleaved sequence at a rate of 2 pps. The CF of acortical site was defined as the frequency at the tip of the V-shapedtuning curve. For flat-peaked tuning curves, characteristic frequencywas defined as the midpoint of the plateau at threshold. For tuningcurves with multiple peaks, characteristic frequency was defined as thefrequency at the most sensitive tip (i.e., with lowest threshold).Response bandwidths 20 dB above threshold of tuning curves (BW20s) weremeasured for all sites. The response latency was defined as the timefrom stimulus onset to the earliest response, using peri-stimulus timehistograms of responses to all tone pips.

The overall boundaries of the A1 were functionally determined usingnon-responsive sites and responsive sites that did not have a welldefined pure tone-evoked response area (i.e., non-A1 sites). To generateA1 maps, Voronoi tessellation (a Matlab routine, The MathWorks, Natick,Mass.) was performed to create tessellated polygons, with electrodepenetration sites at their centers. Each polygon was assigned thecharacteristics (i.e., CF) of the corresponding penetration site. Inthis way, every point on the surface of the auditory cortex was linkedto the characteristics experimentally derived from a sampled corticalsite that was closest to this point.

To document cortical tMTFs, trains of 6 tonal pulses (25 ms durationwith 5 ms ramps at 60 dB SPL) were delivered four times at each of 8repetition rates (2, 4, 7, 10, 12.5, 15, 17.5, and 20 pps) in a randomlyinterleaved sequence. The tone frequency was set at the CF of each site.To reduce the variability resulting from different numbers of neuronsincluded in different multi-unit responses recorded, the normalizedcortical response for each repetition rate was calculated as the averageresponse to the last five pulses divided by the response to the firstpulse. The tMTF is the normalized cortical response as a function of thetemporal rate. The cortical ability for processing repetitive stimuliwas estimated with the highest temporal rate at which the tMTF was athalf its maximum (f_(h1/2)).

Vector strength (34-36) was calculated using the following equation:

vector strength=(1/n)√{square root over (Σ (cos(2πt_(i)/T))²+Σsin(2πt_(i)/T))²)}{square root over (Σ (cos(2πt_(i)/T))²+Σsin(2πt_(i)/T))²)}, where n=total number of spikes, t_(i)(i=1, 2 . . .n) is the time between the onset of the first pulses and the i^(th)spike, and T is the inter-stimulus interval. Spikes that occurred duringa 6T period after the onset of the first tonal pulse were included tocompute vector strength.

The degree of synchronization between cortical sites was assessed byrecording in silence for 10 periods of 10 s spontaneous neuronal spikesfrom two to four electrodes simultaneously. Cross-correlation functionswere computed from each electrode pairs by counting the number of spikescoincidences for time lags of −50 to 50 ms with 1 ms bin size and werenormalized by dividing each of its bins by the square root of theproduct of the number of discharges in both spike trains. Neural eventsoccurring within 10 ms of each other in two channels were consideredsynchronous. The degree of synchronization may be correlated with spikerates in a nonlinear manner. For each pair of spike trains, we estimatedthe number of synchronized events if the two spike trains were notcorrelated, using N_(A)N_(B)ΔT, where N_(A) and N_(B) are the numbers ofspikes in the two spike trains, Δ (=21 ms) is the bin size, and T is theduration of the recording. The strength of the synchrony was thenassessed using a Z-score of the number of synchronous events:

$Z = {\frac{\left( {{{number}\mspace{14mu} {of}\mspace{14mu} {synchronized}\mspace{14mu} {events}} - \frac{{N_{A}N_{B}\Delta}\;}{T}} \right)}{\sqrt{\frac{N_{A}N_{B}\Delta}{T}}}.}$

For neural synchrony recording, offline spike sorting using TDTOpenSorter (Tucker-Davis Technology, Alachua, Fla.) was performed toinclude only single units in the analysis.

Quantitative immunoblotting and ELISA. NE and naïve control rats usedfor quantitative immunoblotting and ELISA were not those used forelectrophysiological experiment but were otherwise treated in the sameway (FIG. 1A). Rats were anaesthetized with an i.p. injection of sodiumpentobarbital (50 mg/kg body weight), and the overall boundaries of theright A1 were functionally determined using electrophysiologicalrecording procedures as above Animals were then deeply anaesthetizedwith an additional dose of sodium pentobarbital. The right A1 and thevisual cortex were rapidly dissected, frozen in dry ice and stored at−80° C. until processing.

For quantitative immunoblotting analysis, synaptoneurosomes wereprepared as described (Hollingsworth E B et al. (1985) J. Neurosci.5:2240-2253) with slight modifications. Equal amounts ofsynaptoneurosomal proteins (7-10 μg), determined using the BCA assay(Pierce, Rockford, Ill.), were resolved in 4-15% polyacrilamide gels andtransferred to PVDF membranes. Membranes were probed with primaryantibodies, followed by the appropriate secondary antibody conjugatedwith infrared dyes (LI-COR Biosciences, Lincoln, Nebr.). Primaryantibodies used were anti-GABA_(A)α1 (1:200, Chemicon, Temecula,Calif.), anti-GABA_(A)β⅔ (1:1000, Upstate, Dundee, UK), anti-myelinbasic protein (MBP) (1:500, USBiological, Swampscott, Mass.), anti-GluR2(1:500, Chemicon, Temecula, Calif.), anti-NR2a (1:400, Upstate, Dundee,UK), anti-NR2b (1:1000, Upstate, Dundee, UK), anti-actin (1:1000,Chemicon, Temecula, Calif.) and anti-γ-tubulin (1:1000, Sigma, St.Louis, Mo.). Immunoreactive bands were visualized and quantified usingOdyssey Infrared Imaging System (LI-COR Biosciences, Lincoln, Nebr.).The relative levels of each protein were calculated as a ratio againsteither actin or γ-tubulin, normalized to those of naïve controls run inthe same gel. Alternatively, the ratio of NR2a/NR2b were used andnormalized in the same way.

For the determination of brain-derived neurotrophin factor (BDNF)levels, fragments of the A1 were lysed and acidified as described(Okragly A J et al. (1997) Exp. Neuro. 145:592-596). Total proteinconcentrations were determined using the BCA assay (Pierce, Rockford,Ill.). BDNF was quantified using an ELISA kit (Human BDNF QuantikineKit, R&D Systems, Minneapolis, Minn.) as per the manufacturer'sprotocol.

For all assays, the researcher was blind to the group identity of thesamples.

Example 1 Changes in Cortical Response S Following Chronic NoiseExposure

In an initial experimental series, rats were exposed to continuous,moderately intense (65 dB SPL) white noise over a 6-week periodbeginning at postnatal week 8 (Pw8). Highly significant differences infrequency tuning, temporal response characteristics and responsecoordination were documented in A1 in these noise exposed (NE) rats(N=7) versus age-matched naïve control rats (N=9) reared under standard,quiet housing conditions (FIG. 1, panel A).

A1 was relatively topographically (tonotopically) organized in controlrats, with isofrequency bands oriented approximately orthogonal to asystematic rostro-caudal frequency representation gradient. A1 tonotopywas distorted in NE rats, to proportionally exaggerate andproportionally reduce the territories representing higher and lowerfrequencies, respectively (FIG. 1, panel B; NE vs. control). Thepercentages of A1 areas tuned to different frequency ranges are shown atthe left in FIG. 1, panel C. The A1 zones best-representing frequencyranges centered at 16 and 32 kHz were significantly larger but the zonesbest representing frequency ranges centered at 2, 4 and 8 kHz weresmaller in NE than in control rats (χ²-test, p=0.033).

Neurons all across A1 responded less selectively (neurons were lesssharply tuned) to sound frequencies in NE than in control rats. Thetuning curve bandwidths measured 20 dB above threshold (BW20s) providedan index of that frequency selectivity, which was significantly andsystematically degraded by this chronic noise exposure (FIG. 1, panel C,right; t-test, all p<0.00012). In addition, cortical response thresholdsfor tonal stimuli were lower in NE than in control rats (19.2±0.5 dB SPLvs. 25.6 ±0.7 dB SPL; t-test, p<0.00001). Response latencies did notsignificantly differ between the two groups (11.4±0.08 ms for NE ratsand 11.5±0.08 ms for control rats; t-test, p=0.39).

Temporal responses in A1 of both rat groups were also examined byrecording cortical responses to characteristic frequency (CF) tonalpulses delivered at variable rates. In control rats, most corticalneurons could follow repeated stimuli at and below rates of 10 pulsesper second (pps) with each successive tone pulse evoking a similarnumber of spikes as did the first tone in the train. By contrast, mostA1 neurons in NE rats only followed stimuli at or below 7 pps (FIG. 2;NE vs. control). For temporal modulation-transfer functions (tMTFs), inwhich normalized cortical responses were defined as a function ofstimulus repetition rates (FIG. 2, inserts), responses decreased at highrepetition rates (i.e., 7-15 pps) in NE compared to control rats (FIG.1, panel D, upper left; t-test, p<0.02-0.00001). A comparison of thedistributions for the highest temporal rates at which tMTF was at halfof its maximum (f_(h1/2), a measure of the cortical capacity forprocessing high rate stimuli) also showed a significant leftward shiftfor NE versus control rats (FIG. 1, panel D, upper right;Kolmogorov-Smirnov test, p<0.001), again demonstrating the decreasedrate-following ability induced by noise exposure, for neurons across allCF ranges (FIG. 1, panel D, lower left; t-test, p<0.0013-0.00001).

To characterize the precision of spike timing relative to stimulusphases, vector strengths were calculated, which quantify the degree ofphase locking of neural responses to successive, identical stimuli.Although the average vector strengths as a function of stimulusrepetition rates followed the same band-pass patterns for both ratgroups, the curve was again shifted leftward and peaked at lowerrepetition rates in NE versus control rats (4 pps vs. 10 pps; FIG. 1,panel D, lower right). Note that vector strengths were smaller at highrepetition rates, but larger at low rates, in NE versus control rats(t-test, p<0.008-0.00001).

Neural synchrony was documented in A1 by simultaneously recording spikeactivity during spontaneous activity periods from neurons withincortical layers 4/5 separated by variable cortical distances (282recording pairs from 4 NE rats; 318 pairs from 5 control rats). Allspikes that occurred in two recording channels within 10 ms of oneanother were considered to be synchronized events. As shown in left ofFIG. 1, panel E, the average correlograms normalized for firing ratesbetween −10 and 10 ms lags differed significantly between the two groups(0.061±0.009 for NE rats and 0.039±0.006 for control rats; t-test,p<0.00001), with a wider temporal dispersion recorded in NE rats. Thedistributed patterns of spontaneous activity correlation reflectingdistributed cortical network coupling also differed significantlybetween them. In the analysis, the observed frequency of occurrence ofsynchronized events for the two neurons was corrected for the expectedchance occurrence of a synchronous event. The resulting average Z-scorefor pairs of simultaneously recorded cortical sites in both groupsdecreased as a function of inter-electrode distances (FIG. 1, panel E,right; ANOVA, both p<0.0001). However, values were higher at allelectrode separations, and correlations were recorded over longercortical distances in NE than in control rats (t-test, all p<0.0005 forseparations ranging from 0.3 to 0.9 mm). Induced changes applied forcortical zones representing low-(<3.1 kHz), middle-(3.1-9.5 kHz), andhigh-(>9.5 kHz) frequencies (FIG. 3; t-test, p<0.035-0.00001).

Example 2 Restoration of Normal Response Properties for Noise-ExposedRats After Being Returned to a Normal Environment

To determine the long-term impacts of noise exposure on A1 responseproperties, three additional NE rats were returned to a normal auditoryenvironment and mapped eight weeks after the end of noise exposure (FIG.4, panel A). BW20 and f_(h1/2) were measured and compared with data fromNE rats recorded immediately after exposure, as well as with data fromaged-matched control rats (N=5). These properties significantly differed(were again reversed) from those recorded immediately after exposure(ANOVA with post-hoc Student-Newman-Keuls test, both p<0.001; FIG. 4,panel B), and were now comparable to data from normal, never-exposedcontrol rats (ANOVA with post-hoc Student-Newman-Keuls test, bothp>0.05). These results manifest a restoration of normal responseproperties for NE rats after their return to a normal acousticenvironment for eight weeks.

Example 3 Noise Exposure Reinstates Corticl Period Plasticity in A1

In the data described to this point, NE rats were exposed to continuousnoise beginning at Pw8. At this age, the rat is approaching sexualmaturity, and A1 has matured far beyond the normal closure of thecritical period window for passive sound-exposure-driven plasticity.Since tone-specific enlargement in A1 representation resulting fromtransient exposure to sound stimuli is a basic index of critical periodplasticity, the post-critical period status of rats at this age wasconfirmed by exposing them to pulsed 7-kHz tone pips over aone-week-long epoch (FIG. 5, panel A). In striking contrast to rats inthe normal early critical period, that exposure resulted in nomeasurable alteration of A1 tonotopy (FIG. 5, panel B).

A subset of NE rats (N=7) were exposed to pulsed 7-kHz tones for oneweek, beginning at the end of their noise exposure epoch (these ratswere thus defined as noise exposed plus tone exposed rats, i.e., NE+TErats; FIG. 6, panel A). As an additional control, another group ofage-matched naïve rats (N=7) were also exposed to pulsed 7-kHz tonesover the same epoch (i.e., TE-control rats; FIG. 6, panel A). The A1zone that selectively responded to 7 kHz was enlarged by mere soundexposure in these NE+TE rats compared to age-matched non-sound-exposedcontrol rats (N=12; FIG. 6, panel B, NE+TE vs. control), just as it isin infant critical period rats. This frequency-specific distortion in A1is illustrated in a second way in FIG. 6, panel C, where CFs of allrecording sites from each group of rats were plotted against anormalized tonotopic axis. Examination of the CF distribution revealedan over-representation of sites tuned to 7 kHz, and a relativeunder-representation of sites tuned to immediately lower and highersound frequencies for NE+TE rats, when compared to control rats (FIG. 6,panel C; NE+TE vs. control). To quantitatively characterize the effectsof pulsed tone exposure on A1 frequency representation, the percentagesof A1 areas representing each frequency range were averaged within thesame experimental group and the differences between exposed and controlanimals plotted (FIG. 6, panel D). Average percentages of A1 areas tunedto 7 kHz±0.25 octave in NE+TE rats were very significantly increasedcompared to control rats (FIG. 6, panel D, NE+TE vs. control; t-test,p<0.00001). It was noted that the magnitudes of these sound exposureinduced changes parallel those resulting from a matched period ofexposure in the critical period in infant rats. As in those infants, thepercentages of A1 areas tuned to frequencies that were just below orjust above the exposed tone frequency were also reduced (t-test,p<0.038-0.005). It is also important to note that the maps and CFdistributions in TE-control rats were not statistically distinguishablefrom those recorded in completely naïve, age-matched controls (FIG. 6,panels B, C, and D; TE-control vs. control).

Example 4 Cortical Plasticitiy Changes in Old Rats

To examine whether noise exposure would induce the same plastic changesin A1 in older rats, the noise exposure protocol was initiated in asecond series of experiments conducted in one-year-old animals. Theserats were again exposed to 7 kHz tonal stimuli immediately after thenoise-exposure epoch (FIG. 7, panel A). A dramatic frequency-specificdistortion in A1 was again evoked by mere passive sound exposure, inNE+TE rats but not in TE-control rats, with both groups again indexed bydata from completely naïve non-exposed rats of the same age (FIG. 7,panels A, B, and C).

Cortical changes induced by passive sound exposure during the criticalperiod in infants are known to be relatively long-enduring. To evaluatethe long-term impacts of tone exposure on cortical representations inthe new sensitive period induced in NE rats, four NE+TE rats werereturned to a normal auditory environment and mapped 7 weeks later (FIG.8, panel A). Percentages of A1 areas tuned to 7 kHz±0.25 octave forthese NE+TE rats were comparable to those of NE+TE rats measured oneweek after the end of the tone exposure (FIG. 8, panel B; ANOVA withpost-hoc Student-Newman-Keuls test, p>0.05) but significantly largerthan that of control rats (ANOVA with post-hoc Student-Newman-Keulstest, p<0.001). Thus, as in the early postnatal critical period, theplasticity changes induced by tonal exposure following noise exposurepersisted with little change for up to at least 7 weeks after thatexposure.

Example 5 Molecular Changes in A1 Induced by Noise Exposure

To begin to document the auditory system changes that paralleled there-establishment of the critical period, levels of cortical inhibitionand excitation were documented in NE and control rats by usingquantitative immunoblotting. Antibodies that recognize α1 and β⅔subunits of gamma-aminobutyric acid A (GABA_(A)) receptors were used toassay changes in cortical inhibition. Antibodies that recognize theGluR2 subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate(AMPA) receptors and the NR2a and NR2b subunits of N-methyl-D-aspartate(NMDA) receptors were used to track changes in cortical excitation.Quantitative immunoblotting revealed a significant decrease inexpression levels of both oil and ⅔ for NE rats compared to control rats(FIG. 9, panel A; t-test, both p<0.004). Changes in GluR2, or in theratio of NR2a/NR2b of NE rats versus control rats did not reach thelevel of statistical significance (FIG. 9, panel B; t-test, bothp>0.17). Cortical myelin basic protein (MBP) levels were also measuredusing quantitative immunoblotting, and brain-derived neurotrophin factor(BDNF) levels using an enzyme-linked immunosorbent assay (ELISA). Adecreased expression of MBP and an increased expression of BDNF wererecorded in cortical field A1 of NE rats compared to control rats (FIG.9, panel C; t-test, p=0.0002 for MBP and 0.04 for BDNF). These molecularchanges in A1 were all substantially or completely reversed to normaladult titers by returning NE rats to a normal acoustic environment foreight weeks after the end of noise exposure (N=6 of NE rats and N=5 ofcontrol rats for each group; t-test, all p>0.06). As an intra-braincontrol, the expression levels of α1, β⅔ and MBP were quantified in theoccipital visual cortex in NE and control rats. No significantdifferences were seen (FIG. 10; t-test, all p>0.26).

Discussion

For more than 50 years, the neuroscience mainstream has viewed braindevelopment as a multiple-stage process that begins with a pre-criticalperiod epoch, advances into a relatively short-duration, highly plasticcritical period, then progresses relatively abruptly into a thirdaplastic or less plastic adult phase. That critical period is usuallydescribed as a developmental stage during which mere exposure to visualor sound or tactual or other stimuli drives substantial neurologicalspecialization or change. The evidence provided herein supports a majorrevision in our understanding of these change progressions: at leastmost of the very complex chemical, physical and functional changesresulting in the transition to an adult stage are, by their nature,reversible.

In this study, a great capacity for naturally driving “negative”cortical changes was documented when post-critical period rats wereexposed over a several-week-long period to continuous, moderate-levelnoise. A wide range of fundamental plastic changes in excitatory andinhibitory neuronal processes were here documented to occur in thecortex, and in most respects, after this exposure, A1 re-acquiredcharacteristics that apply for this cortical area in the critical periodin a less mature (infantile) state. A1's inhibitory processes weredown-regulated; it was producing less myelin (MBP); a primary trophicfactor that contributes critically to vigorous critical periodplasticity, BDNF, was again up-regulated; spectral responses were lessselective; representational topography favored high and disfavored lowfrequency representations; temporal responses were sluggish, andimprecise at higher input rates; cortical activities were moretemporally and spatially dispersed. All of these aspects of corticalfunction and structure moved in the direction of the “more immature” A1.Moreover, this complex series of changes was again paralleled by anemergent sound-exposure-sensitive epoch—a new “critical period”—in theserats. The plastic distortion induced in juvenile animals was of the samemagnitude as that generated in an infant critical period rat. This soundexposure-induced remodeling endured in the cortex, just as it does wheninduced in the infant critical period. Identical reversals in theindices of cortical maturation were also recorded in older rats,strongly indicating that these many aspects of cortical maturation canregress at any age in life. On the other hand, when the cortex wasallowed to again progress in its organization by returning the animalback to a normal acoustic environment, A1 again evolved back to an adultstatus reflected by a re-reversal of the indices of maturity describedabove—changing in them, just as it does in the transition from thecritical period to the adult stage, in a normal early life.

Chronic passive exposure to a special form of noise (very rapid,randomly delivered tonal stimuli) can result in broadened frequencytuning and increased neuronal synchrony in A1 zone representingfrequencies of exposed tones in adult cats. In this study thenoise-induced changes actually re-opened a new sensitive or criticalperiod, and a wide array of complex changes were found to be reversed byreturning these young now-adult animals into a normal acousticenvironment. The recovery from the “negative plasticity” changes inducedby noise were distinguished from the positive, persistent corticalchanges induced by transient sound exposure during the critical period,in that the latter changes do not rapidly fade, but to the contrary,persist long after they are induced.

The degree of critical period-like plasticity is believed to be atitrated function of the level of GABA_(A) activity. Cortical inhibitioncan also play an important role in shaping neuronal processing in A1, asin the visual cortex. The mature, functionally-differentiated cortex,with its strongly and powerfully-selective inhibitory processes inplace, responds with greater cooperativity, reliability and predictably.This study indicates that the processes degrading GABA_(A) inhibitionand therefore enabling plasticity trade off against response reliabilityand stability, and indicates that this tradeoff is subject to continuousfluctuation over the course of a lifetime. Ongoing studies are designedto define strategies for manipulating this “set point” for plasticity inolder brains, and for further elucidating the many theoretical andpractical implications of these findings.

Finally, it should be noted that this study also illustrates potentiallydestructive consequences of even moderate-level noise exposure for therepresentations of auditory

GABAergic inhibition, NMDA receptors, and BDNF can play important rolesin regulating or enabling changes that express that transition. Here, werecorded reversible changes in both GABA_(A) α1 and β⅔ subunits; BDNF.It might be noted that one index of cortical maturity measured in thisstudy, the proportional levels of expression of NMDA receptor NR2a andNR2b subunits did not change following noise exposure.

In the visual cortex, reduction of GABAergic inhibition can re-open aperiod of stimulus exposure-based plasticity, revealing a conservedpotential for plasticity carried into adulthood. Similarly, returningolder rats to continuous darkness can also re-open an epoch of oculardominance plasticity. Again, changes in GABA_(A) inhibitory processeswere recorded in parallel with this apparent critical period re-opening.The embryonic Otx2 homeoprotein controls changes in parvalbumin GABA_(A)neurons that may open and close the critical period in the visualcortex. Changes in A1 responses following noise exposure (i.e., degradedfrequency tuning and more sluggish temporal responses) are similar tothose resulting from reduced cortical GABAergic inhibition.Immunoblotting data revealing a decrease in the expression level ofGABA_(A) α1 and β⅔ subunits in A1 of NE rats, and the restoration oftheir levels after the post-noise-exposure recovery of theseinhibition-dependent response characteristics all support thisconclusion that parvalbumin-containing neurons and other processesinvolving GABA_(A) receptors have also been weakened by chronic noiseexposure. The precision of neuronal synchronization is also influencedby the status of GABAergic inhibition. Synchronization as a function ofcortical distance is a function of the degree of receptive field overlapacross cortical networks. Thus, the changes in the precision anddistribution of coordinated responses recorded here are also bothconsistent with cortical “detuning” arising from, or at least paralleledby the significantly weakening of GABA_(A) inhibition.

In addition, noise exposure was found to reduce the expression level ofcortical MBP, another marker of the progression from an infantile to themature cortical status. Myelination can also play a key role in theregulation of CNS plasticity. During early development, its elaborationat the end of the critical period actively suppresses mereexposure-driven plasticity, and in the mature nervous system, myelinproteins are potent but reversible inhibitors of axonal re-growth andnew synapse formation after injury. The decrease in MBP observed in A1after noise exposure suggests that myelin levels are actively andcontinuously regulated in the cortex in an activity-dependent manner topromote or limit permissive states of stimulus exposure-driven change.Based on the study presented herein, intracortical myelination canincrease the timing precision of the neuro-modulation of plasticity,thus contributing to the enabling of learning context-,outcomes-dependent plasticity, which is another consequence of thetransition to adult plasticity.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

What is claimed is:
 1. A method for inducing brain plasticity in anindividual comprising: presenting to said individual continuous noiseover a period of time; and providing said individual with tonesensitivity training or language training.
 2. The method of claim 1,wherein said noise is structured noise.
 3. The method of claim 1,wherein said period of time is about 6 weeks.
 4. The method of claim 1,wherein said individual is about 20 months or younger.
 5. The method ofclaim 1, wherein said individual has suffered or is suffering from aneurological injury.
 6. The method of claim 1, wherein said individualis dyslexic.
 7. The method of claim 1, wherein said method increasesadaptability of auditory cortex in said individual.
 8. The method ofclaim 1, wherein said noise is presented at about 65 dB.
 9. The methodof claim 1, wherein said method further comprises placing saidindividual in a normal auditory environment after said presenting step.10. The method of claim 1, wherein presenting is done by a cochlearimplant.
 11. A cochlear implant that performs the method of claim
 1. 12.A computer accessible memory medium comprising program instructions forinducing brain plasticity in a subject, wherein said execution of saidinstructions causes a device to perform the method of claim
 1. 13. Amethod for inducing brain plasticity in an individual comprising:executing an instruction in an electronic device to present to saidindividual continuous noise over a period of time; and executing aninstruction in an electronic device to provide said individual with tonesensitivity training or language training.
 14. The method of claim 13,wherein said noise is structured noise.
 15. A computer-readable storagemedium for inducing brain plasticity in an individual, comprisinginstructions executable by at least one processing device that, whenexecuted, cause the processing device to: (a) present to the individualwith continuous noise over a period of time; and (b) provide saidindividual with tone sensitivity training or language training.
 16. Thecomputer-readable storage medium of claim 15, wherein said noise isstructured noise.
 17. The computer-readable storage medium of claim 15,wherein said period of time is about 6 weeks.
 18. The computer-readablestorage medium of claim 15, wherein said noise is presented at about 65dB.